Post-Traumatic Stress Disorder (PTSD) is a debilitating anxiety disorder that negatively affects the lives of men and women worldwide. The diagnosis of PTSD requires exposure to a traumatic or life- threatening event with persistent symptoms of hyperarousal, re-experiencing, avoidance, and negative cognition and mood. Although a large portion of the population is exposed to a traumatic event sometime during their lifetime, only about 15-30% develop PTSD. Among those that do, rates of co-occurring substance use disorder and/or alcohol use disorder are 3-4 times higher than in the general population. Despite the appreciation that PTSD increases susceptibility to substance and alcohol use, little is known about the biological basis of this co-morbidity. If the mechanism of the increased susceptibility to substance use is identified, then treatment approaches could be applied to help prevent or reduce the incidence of substance abuse and addiction in persons with PTSD. Several excellent rodent models of traumatic stress have been developed, however they have been inadequate to model the elevated drug- seeking behaviors that occurs in humans. This has restricted the ability of researchers to elucidate underlying biological mechanisms that increase susceptibility to drug and alcohol use in the setting of PTSD. We hypothesize that this is due to the failure to consider individual responses to the traumatic stress. Similar to the clinical situation where only a subpopulation of trauma-exposed people develop PTSD, only a subpopulation of trauma-exposed animals shows extreme behavioral phenotypes reminiscent of PTSD. Thus, the goal of this project is to establish methods that recapitulate the behavioral phenotypes of both PTSD and drug and alcohol use disorders, which is critical to determine the causative neurobiology of this co-morbidity and for its eventual treatment. The goal will be achieved by behavioral profiling of out-bred rats exposed to the single prolonged stress (SPS) model of PTSD, in order to select those subjects with a phenotype of persistent high anxiety and exaggerated trauma cue responses. The Aims of this project will determine if the SPS-susceptible rats show high rates of cocaine self-administration and voluntary ethanol consumption as compared with SPS-resilient and non-stress controls, thus establishing a robust model of co-occurring PTSD and substance/alcohol abuse. Potential sex differences in the prevalence of co-occurring high stress reactivity and high cocaine- and alcohol- seeking behaviors will be investigated.